Peripherally Acting Skeletal

Muscle Relaxants

By: Pradeep Singh & Abhimanyu Meena

 Skeletal Muscle Relaxation, Why
Clinically ?
In conjugation with General Anesthetics:
• Facilitate intubation of the trachea
• Facilitate mechanical ventilation
• Optimized surgrical working conditions

d Atamy
y

History of Skeletal Muscle Relaxants

• Curare is a common name for various plant extract alkaloid arrow

poisons originating from Central and South America.
• Source: Chondrodendrone tomentosum and Strychnos toxifera
• Tubocurarine name because of packing in "hollow bamboo tubes"
 Classification
Skeletal muscle relaxants

Centrally acting Peripherally acting

• Diazepam and oth er
ben zo d iazep in es
• Methocarbamol
• Chlorzoxazone
• Tizanidine
• Baclofen Drugs acting at Drugs directly acting
• Gabapentin NMJ on skeletal muscle
• Dantrolene
I
t %
Depolarizin Non-depolarizing blockers Ot h er s
g blockers (Competitive blockers) • Botulinum
• Succinylcholine toxin A
• d-TC }
• Decamethonium •
• Pancuronium Long acting
• Doxacu ri um
P ipecuroniu
• Vecuronium }
m
• Atracurium Intermediate acting
• Rocuronium
• Mivacurium Short acting
 Acetylcholine

• Acetylcholine is a major neurohumoral transmitter at

autonomic, somatic and central nervous system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
2. Skeletal Muscles
3. CNS: Cortex Basal ganglia, spinal cord and others
Parasympathetic Stimulation - Acetylcholine (ACh)
release at neuroeffector junction - biological effects
Sympathetic stimulation - Nonadrenaline (NA)
at neuroeffector junction - biological effects
 0 H 3C

Acetylcholine H.C
) O
... ..'.·N·."

l
CH'•3
3
\ ' CH 3

Sympathetic Parasympathetic

Ach
Preganglionic fibers Preganglionic fibers
Acetyicholine
(short) (long)

k4 Ach

4
Nicotinic receptor

t4
Muscari Ach

4
nic
recepto
r

Norepinephrine

Posganglionic fibers Posganglionic fibers

NE Ach

EA
PharmacologyCorner. com
Neuromuscular Junction (NMJ)
NMJ

Nerve
termin kA C h ,
al
• %
ACh AChE
rece ,"
ptor
s
End plate
Muscle
Physiology of Skeletal Muscle
Contraction
Motor nerve impulse

i
Release of acetyMcholine

•
Binds with N, receptors at

•
developme of end-plate potential (EPP)
NMI
at motor end plate (Mainly due to influx of Na' )

Depolarization and
•
nt p otential (MAP) •
Muscle-action
Contraction of skeletal muscle

ACh is rapidly inactivated by cholinesterase

leading to repolarization

Muscle is ready for • a fresh nerve

 Peripherally acting:
Neuromuscular Blockers

• Depolarizing Blockers - mimic the action of

acetylcholine (ACh)
- Agonists
- Succinylcholine (SCh) is the only drug used clinically

• Non-Depolarizing - interferes with the action of

ACh
- Competitive Blockers (Antagonist)
- Further divided into short, intermediate and long acting
non- depolarizing drugs
 Depolarizing Block - Succinylcholine

• Succinylcholine have affinity and sub-maximal

intrinsic activity at Nm receptor.
• It acts on sodium channels, open them and
causes initial twitching and fasciculation.
• It does not dissociate rapidly from the
receptors resulting in prolonged
depolarisation and inactivation of Na+
channels.
 Mechanism of Action: Succinylcholine

Ni coti n i ACh Receptor

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8

a •¥
Coed
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Inside

Na'
 Succinylcholine acts on the Nicotinic receptors of
the muscles, st im ulat es them and ult imat ely
cause

►This process occur in two phases :

their relaxation.

• Phase I: Dur ing Phase I (depo lar izing phase), t hey

cause
muscular fasciculations while they are depolarizing the
muscle fibers.

• Phase 11: After sufficient depolarization has occurred,

phase 11 ( desensit ized phase) set s and t he muscle
is no
longer responsive to Ach released by the nerve
endings.
PHASEI
Memb rane depolariz es,
resulting
in an initial discharge that
produces transient fasciculations PHASE II
followed by flaccid paralysis. Membrane repolarizes, but

d
receptoris desensitized
Succiny!• to the effect of acetylcholine.
choline

..
4 «

Nicotinic receptor at a
... •
neuromuscularjunctio Na
n
 Succinylcholine
Advantages:
• Most commonly used for Tracheal intubation
• Rapid onset (1-2 min)
• Good intubation conditions - relax jaw, separated vocal chords with
immobility, no diaphargmatic movements
• Short duration of action {5-10 minutes)
• Dose 1-1.Smg/kg
• Used as continous infusion occasionally

Disadvantages:
• Cardiovascular: unpredictable BP, heart rate and arrhythmias
• Fasciculation
• Muscle pain
• Increased intraocular pressure
• Increased intracranial pressure
• Hyperkelemia: k+ efflux from muscles, life threatening in Cardiac Heart Failure,
patient with diuretics etc
 Non-Depolarising Drugs

• Competitive Blockers having no intrinsic

activity (antagonist)
• These are of 3 types based on their
activity:
- Long Acting: d-TC, Pancuronium, Pipecuronium,
Gallamine (Kidney Excretion)
- Intermediate: Vecuronium, Rocuronium,
Atracuronium (eliminated by liver)
- Short Acting: Mivacuronium, Ropcacuronium
(inactivated by plasma cholinesterase)
 Mechanism of Action:
Non-depolarizing Block in Muscles

3
High dose

c..
ACh
a.
..s
~
sos[]

N,:(a1)016v

o
Drawing Adapted f rom Karli n A: Nature Reviews Neurosc ience 3, 102-114 (F ebruary 2002)
Pentameric data from. Mi llar NS. Assembly and subunit diversity of nicotinic
acetylch oline
receptors. Biochem Soc Trans 31:869, 2003.
 Mechanism of Action
• They have affinity but no intrinsic activity for Nicotinic receptors
(Antagonist)
• They are quat er nary N+ com pounds t hat cont ain cat io nic head t hat
act only on closed Na+ channels - No act io n on already opened
Na+ channels
• The cationic head binds to the anionic ACh binding site at the a -
subunit of the Nm receptor but cannot bring conformational change
& Na+ channels remians closed
• No End Plate Potential generation in nerve endings
• Muscle Action Potential decreases
• Act io n can be overcome by
increased ACh concent rat io n or
• blo cking of acet y lcholinest erase
They also block prejunctional ACh receptors on motor nerve
endings - FADE PHENOMENON
 Acetylcholine
O O Nondepolarizing blocker

a
Depolarizing blocker

-=
IH

t
choice · / ] N a
n
A c a .
A ChE 7 . ,...,
'. - - - -

_,.

...,...,. .._._,_ D
E n d plate
s t
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ts
Ill D
t
Channel closed Channel open normal

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er
N a II
t
A c e t a t e /
Acne_8
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End plate
s rt
I Ill t

1
cs

Channel closed Channel open blocked

 Effects of Non-depolarizing blockers

• Low Doses:
- Competitive antagonists of ACh
- Action reversed by ACh ecterase inhibitors

• Large Doses:
- Ion Channel is blocked
- More weakness of neuromuscular transmission
- Action could not be reversed by ACh esterase inhibitors

• Other actions:
- Can block pre-junctional Na+ channels and interfere with
mobilization of ACh at nerve endings
 Non-depolarizing Drug:
d-Tubocurarine
• 1° agent to undergo clinical
• invest igat ion
purified curare - Chondodendrom
tomentosum
•
ED%,= 0.5mg/kg
• undergoes minimal metabolism- is excreted
- 10% in urine
- 45% in bile
• excretion impaired in Renal Failure
 CV Effects:
S
hypotension frequently even at doses <
• ED%,
• histamine released (skin flushing
frequently)
• autonomic ganglionic blockade- manifests
as hypotension

Clinical Use:
• long duration of action(60 to 120 mins) and CVS
effects restricted its use
used as "precurarization"
 Non-depolarizing Drugs

• Gallamine
- Less potent than curare
- Tachycardia

• D-Tubocurarine
- 1-2 hr du ration of action
- Hist am ine releaser (Brochospasm,
- hypot ensio n) Blocks aut ono mic ganglia
(Hy pot ensio n)
• Atracurium
- Rapid recovery
- Safe in hepatic & renal impairment
- Spontaneous inactivation to laudanosine (seizures)
 Non-depolarizing Drugs

• Mivacurium
- Metabolized by pseudocholinesterase
- Fast onset and short duration

• Pencuronium
- Long duration of action
- Tachycardia

• Vecuronium
- Intermediate duration of action
- Fewer side effects (no histamine release, no ganglion
blockade, no antimuscarinic action)
 I. - .. -musc
D 'i re nce competitive
d larisinn and
l a ~cker
between
Blockade type Competitive blockade Depolarising blockade

Type of relaxation Flaccid paralysis Fasciculation followed by

paralysis
Neostigmine addition + antagonism Potentiation

Effect of other Decreased effect Increases effect

neuromuscular blocking
drug
Histamine release ++ release negligible

Serum k+ level No change Hyperkalemia

Pharmocogenetic nil pesudocholinesterase

variation
Cardiac M2 receptor No effect stimulate (bradycardia )
 Other Actions of Blockers
Nm
• Automic ganglia:
■ Part ial blockage of ganglia (Nm of receptor)
type
■ Result s in fall in BP and
• tachycardia

Histamine release: salivary secretion

■ Hy pot ension
• Cardiovascular: Fallexcess
■ Bronchospasm, in BP due to
bronchial
and
■ Ganglion blockage, hist am ine release and reduced
veno us
return
■ Succinylcho line may cause cardiac ar rhyt hmias
• GIT:
Paralytic ileus
 Pharmacokinetics of blockers
Nm
• Polar quaternary compound - Not absorbed orally, do not
cross cell membranes, Blood Brain Barrier or placental
bar rier, low Volume distribution - always given
of int raveno usly or intramuscular
• rarely
Muscles with high blood flow affect earlier
• Redistribution to non muscular tissues occur and action
may persist longer than half life
• Drugs metabolised in plasma/liver (d-TC and pancuronium)
- 60-120 min
• Succinylcholine ) Succinylmonocholine ) Succinc
acid+ choline (plasma cholinesterase): 3-5 min
• In some - generally determined abnormality and deficient
pseudocholinesterase ) Paralysis & apnoea
Directly acting relaxants - Dantrolene

• Different from neuromuscular blockers, no action on

neuromuscular transmission
• Mechanism of Act io n: Ryanodine recept ors (RyR)
calcium channels - prevent s depolar izat io n - no
int racellular release of Ca++
• Absorbed orally, penetrate brain and produces sedation,
metabolized in liver, excreted in kidney. T%. 8-12 hrs
• Dose: 25-l00mg - 4 times daily
• Uses: Upper Motor Neuron disorders - paraplegia,
hemiplegia, cerebral palsy and malignant hyperthermia
(drug of choice 2.5-4 mg/kg)
• Adverse effects - Sedation, malaise, light
headedness, muscular weakness, diarrhoea and
hepatotoxicity
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References
• Essentials of Pharmacolgy - KD Tripathi
• Pharmacology - Tara V Shanbhag
• http ://www.sl idesha re. net/d rd h riti/skeleta I-m use I e•
re laxants-2011-d rd h riti?qid =91efc8a9-ea87-481d•
a77c-cObdd42f0932&v=&b=&from search=1
 ThankYou !!!

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